Briarane-type diterpenoids suppress osteoclastogenisis by regulation of Nrf2 and MAPK/NF-kB signaling pathway

Junjun Meng; Xu Zhang; Xingchen Guo; Wei Cheng; Xinyi Qi; Jian Huang; Wenhan Lin

doi:10.1016/j.bioorg.2021.104976

Briarane-type diterpenoids suppress osteoclastogenisis by regulation of Nrf2 and MAPK/NF-kB signaling pathway

Bioorg Chem. 2021 Jul:112:104976. doi: 10.1016/j.bioorg.2021.104976. Epub 2021 May 7.

Authors

Junjun Meng¹, Xu Zhang², Xingchen Guo¹, Wei Cheng¹, Xinyi Qi¹, Jian Huang³, Wenhan Lin⁴

Affiliations

¹ State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, PR China.
² Institute of Ocean Research, Ningbo Institute of Marine Medicine, Peking University, Beijing, PR China.
³ State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, PR China. Electronic address: jhuang@bjmu.edu.cn.
⁴ State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, PR China; Institute of Ocean Research, Ningbo Institute of Marine Medicine, Peking University, Beijing, PR China. Electronic address: whlin@bjmu.edu.cn.

PMID: 33992967
DOI: 10.1016/j.bioorg.2021.104976

Abstract

Excess osteoclastic activity leads to an imbalance in bone remodeling and causes most adult skeletal diseases. Natural products are a promising source to attenuate the osteoporosis and relevant diseases of bone loss. Herein, a bioassay-guided detection of gorgonian corals resulted in junceellolide D (JD), a briarane-type diterpenoid from gorgonian Dichotella gemmacea, showing significant inhibition against the receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation in bone marrow macrophages (BMMs) in vitro. To extend the investigation for structure-activity relationship (SAR), a total of 39 briarane-type analogues were isolated including 28 new compounds, and their structures were determined by extensive analyses of spectroscopic data. The SAR data indicated that JD is the most active to inhibit osteoclast development due to the decreased number of multinucleated tartrate-resistance acid phosphatase positive cells, suppression of the actin ring formation, blockage of bone resorption, and downregulation of osteoclast-specific marker genes. Mechanistically, JD increased the protein stability of nuclear factor (erythroid-derived 2)-related factor-2 (Nrf2) and promoted Nrf2 nuclear translocation followed by activation its downstream antioxidant enzymes, which strongly abolished RANKL-induced generation of reactive oxygen species (ROS). Furthermore, JD inhibits the RANKL-stimulated activation of NF-κB and MAPK signaling pathways. Hence, JD is considered as a promising lead compound for anti-osteoclastogenesis via activating Nrf2 and suppressing NF-κB and MAPK signaling pathways to prevent osteoclast-mediated bone destructive diseases.

Keywords: Briarane-type diterpenoids; Junceellolide D; MAPK; NF-κB; Nrf2; Osteoclastogenisis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anthozoa / chemistry*
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / isolation & purification
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Dose-Response Relationship, Drug
Humans
MAP Kinase Signaling System / drug effects
Molecular Structure
NF-E2-Related Factor 2 / antagonists & inhibitors*
NF-E2-Related Factor 2 / metabolism
NF-kappa B / antagonists & inhibitors*
NF-kappa B / metabolism
Osteogenesis / drug effects*
Signal Transduction / drug effects
Structure-Activity Relationship

Substances

Anti-Inflammatory Agents, Non-Steroidal
NF-E2-Related Factor 2
NF-kappa B
NFE2L2 protein, human